DESCRIPTION: It is stated that the long term objectives of this proposal are to identify structural features in antimalarial dispiro-1,2,4,5-tetraoxanes associated with high intrinsic antimalarial activity, metabolic stability, good oral bioavailability, and low neurotoxicity. To partially address these objectives, the principal investigator hypothesizes the following: i) oral bioavailability in dispiro-1,2,4,5-tetraoxanes is a function of their metabolic stability, and ii) bridged and fluoro-substituted dispiro-1,2,4,5-tetraoxanes might possess resistance to inactivating drug metabolism via steric and electronic stabilization, respectively. The specific aims are to: (1) Synthesize and characterize eight bridged and five fluoro-substituted dispiro-1,2,4,5-tetraoxanes via acid-catalyzed peroxyketalization of the appropriate cyclohexanone derivatives. (2) Determine metabolic stability for the dispiro-1,2,4,5-tetraoxanes described in specific aim (1) and for the ten dimethyl and tetramethyl dispiro-1,2,4,5-tetraoxane regioisomers (said to be available from previous work) in a liver microsome metabolic model using a quantitative GC assay. (3) Screen all of the dispiro-1,2,4,5-tetraoxanes described above for intrinsic antimalarial activity against Plasmodium falciparum in vitro. (4) Determine an in vivo indirect measure of relative bioavailability for active dispiro-1,2,4,5-tetraoxanes described above by measuring % parasitemia (day six-post infection) after both subcutaneous and oral administration of a divided dose of 64 mg/kg drug (days 3,4,5-post-infection) using Plasmodium berghei infection.